Critically-ill patients suffering from acute sepsis are at immediate risk of death. The current management approaches for these patients depend on the use of corticosteroids, antibiotics, fluid resuscitation, and supportive care for failing organs. However, these interventions are not efficacious enough to achieve a 100% protection of patients against organ failures and death. The mortality rate of patients with severe sepsis is about 50%, and can reach 90% if septic shock results.
Bacterial lipopolysaccharide (LPS) is a structural component of the outer cell membrane of the bacterial cell wall. Once being released in circulation, free and biological active LPS molecules stimulate monocytic cells to release pro-inflammatory cytokines. Controlled and localized releases of these cytokines help the host immunity to mount inflammatory responses to get rid of the invading pathogenic bacteria. However, in response to severe overwhelming bacterial infection, un-checked and widespread releases of pro-inflammatory cytokines can result in deleterious activation of coagulation systems and leukocyte-mediated reactions that ultimately lead to multiple organ failure and even death. Hyper-activation on the coagulation leads to thrombosis, tissue hypoxia, and necrosis. Meanwhile, extravasation and tissue infiltration of inflammatory leukocytes are also stimulated. The infiltrated leukocytes cause tissue damages by many different cellular mechanisms like generation of reactive oxygen species which damage the plasma membrane.
Based on the current understanding of sepsis pathogenesis, therapeutic agents that are able to reduce the release of pro-inflammatory cytokines through blocking the initial LPS stimulation on the host immune system, and/or the infiltration of leukocytes into tissues are likely to benefit the survival of patients with acute sepsis.
Thus there remains a need for additional therapeutics for treatment of critically ill patients with acute peritonitis and sepsis in emergency units.